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MAb Passive Vaccination against Acinetobacter baumannii

针对鲍曼不动杆菌的 MAb 被动疫苗接种

基本信息

批准号：
10634737
负责人：
BRAD J SPELLBERG
金额：
$ 78.8万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-25 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10634737
关键词：
Acinetobacter baumannii Adoption Amino Acid Sequence Anti-Bacterial Agents Antibiotic susceptibility Antibiotics Antibodies Bacteremia Bacteria Binding Biological Assay Blood CLIA certified Cells Cessation of life China Clinical Clinical Microbiology Clinical Trials Collection Death Rate Developed Countries Development Dose Drug resistance Ensure Europe Evaluation Exposure to Future Goals Grant HL60 Health Care Costs Human Immune system In Vitro Individual Infection Inflammatory Response International Laboratories Lead Leukocytes Lung infections Macrophage Manuals Mediating Modeling Multivariate Analysis Mus Outcome Patients Phase Phase I Clinical Trials Plasma Predisposition Progress Reports Proteins Regimen Reporting Resistance Sepsis Serum South America Southeastern Asia Surrogate Markers Surveys Taiwan Testing Therapeutic Therapeutic Monoclonal Antibodies Time Toxic effect Translations Vaccination Vaccines Work bacterial resistance capsule clinical development cytokine efficacy evaluation high throughput screening improved outcome in vivo in vivo evaluation infection rate lead candidate manufacturing cost news novel operation pathogen pneumonia model preclinical development prevent rapid test research clinical testing statistics synergism uptake virtual

项目摘要

PROJECT SUMMARY/ABSTRACT In contrast to other resistant bacteria, virtually no antibiotics are in the pipeline to deal with XDR A. baumannii. There is a critical need for new strategies to prevent and treat these infections. We spent the first grant period raising MAbs to A. baumannii capsule, and have now identified 4 anti-capsular MAbs (2 of which were used to generate a bi-specific MAb, leaving us with 3 MAb molecules) that collectively bind to 80-90% of US clinical isolates and protect mice from lethal infection. These 3 lead candidates are all highly potent, achieving 100% protection in bacteremia models at single doses of ≤ 50 µg. They are also protective in pneumonia models of infection, and synergize with antibacterials. Furthermore, the bi-specific MAb has increased potency compared to each of its individual MAbs, and retains binding for all target strains, and efficacy in vivo. This lead three- MAb therapeutic has begun translation into full GMP and toxicity, planning for a future Phase I clinical trial. Our goals for the renewal are to enhance feasibility of clinical development and deployment of the MAbs by closing any coverage gaps against international strains, defining surrogate efficacy markers, and validating key assays to support clinical trials and future clinical deployment. We have obtained a new global strain collection, and entered into key partnerships to further these aims, including experts at multi-valent MAb synthesis, clinical microbiology laboratory operations, and statistics. Our Aims are to: Specific Aim 1: Define and optimize strain coverage and surrogate efficacy markers for international clinical strains of A. baumannii. We have collected 50 strains each from Taiwan, Southeast Asia, China, Europe, and South America. We will survey our 3 MAbs against all acquired strains, assessing flow binding and macrophage uptake, and will assess efficacy in our IV bacteremia model for representative strains. We will raise news MAbs as needed to close international strain coverage gaps. Specific Aim 2: Validate bioassays to enable clinical trials of the MAbs, including potency and human surrogate efficacy markers. We will validate LC-MS/MS for the specific amino acid sequences of our variable regions to quantify our MAbs when spiked into human blood, distinct from background antibodies. We will adapt our well-established HL-60 assays to quantify opsonic activity of MAb in human plasma. Finally, we will use multiplex Luminex assays to quantify cytokine modulation of fresh human leukocytes. Specific Aim 3: Optimize a rapid in vitro binding assay as a “susceptibility testing”-equivalent to support clinical trials and deployment of the MAbs. We will validate rapid, high throughput flow binding assays to correlate with protection in mice as a “susceptibility-test equivalent”. Novel solutions for A. baumannii infections are a critical unmet need. We have developed a promising MAb regimen that improves outcomes during blood and lung infection in mice. We will define global strain coverage, close any identified gaps, and develop bioassays to support clinical testing of the MAbs.

项目摘要/摘要与其他耐药细菌不同的是，几乎没有抗生素正在研制中，以应对鲍曼不动杆菌。迫切需要新的战略来预防和治疗这些感染。我们花了第一个资助期将单抗提高到鲍曼不动杆菌胶囊，现已鉴定出4株抗包膜单抗(其中2株用于产生一种双特异性单抗，留给我们3个单抗分子)，它们共同结合80%-90%的美国临床隔离和保护小鼠免受致命感染。这3个领先候选人都是非常有潜力的，达到了100% 单剂量≤50微克对菌血症模型的保护作用。它们对肺炎模型也有保护作用感染，并与抗菌药协同作用。此外，与双特异性单抗相比，双特异性单抗的效价更高。对其每个单独的单抗，并保留对所有目标菌株的结合，并在体内有效。这一领先优势为3- MAB治疗已经开始转化为完整的GMP和毒性，并计划未来的I期临床试验。我们更新的目标是增强临床开发和部署的可行性通过缩小针对国际毒株的任何覆盖差距，定义替代效力标记，以及验证支持临床试验和未来临床部署的关键分析。我们已经获得了一个新的全球菌株收集，并为实现这些目标建立了关键伙伴关系，包括多价单抗方面的专家综合、临床微生物学实验室操作、统计。我们的目标是：具体目标1：确定和优化菌株覆盖率和替代药效标记鲍曼不动杆菌临床分离株。我们收集了台湾，东南亚，中国，欧洲和南美。我们将针对所有获得的菌株检测我们的3株单抗，评估流动结合。和巨噬细胞摄取，并将评估在我们的IV菌血症模型中对代表菌株的疗效。我们将根据需要筹集新闻单抗，以缩小国际压力报道差距。具体目标2：验证生物测定，以便能够对单抗进行临床试验，包括效力和人体试验代用功效标记物。我们将验证LC-MS/MS对我们的不同于背景抗体的可变区，用于量化我们的单抗在注入人体血液时的数量。我们将采用我们成熟的HL-60分析方法来定量人血浆中单抗的光学活性。最后，我们将使用多重Luminex分析来量化新鲜人类白细胞的细胞因子调节。具体目标3：优化快速体外结合试验作为“药敏试验”--相当于支持单抗的临床试验和部署。我们将验证快速、高吞吐量的流绑定检测与对小鼠的保护相关联，将其视为“敏感性测试等价物”。针对鲍曼不动杆菌感染的新解决方案是一个关键的未得到满足的需求。我们已经研制出一种很有前途的单抗在小鼠血液和肺部感染期间改善结果的方案。我们将定义全球菌株覆盖范围，填补任何已确定的差距，并开发生物检测方法，以支持单抗的临床测试。

项目成果

期刊论文数量（28）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Antimicrobial Susceptibility Testing Performed in RPMI 1640 Reveals Azithromycin Efficacy against Carbapenem-Resistant Acinetobacter baumannii and Predicts In Vivo Outcomes in Galleria mellonella.

DOI：
10.1128/aac.01320-22
发表时间：
2023-01-24
期刊：
Antimicrobial agents and chemotherapy
影响因子：
4.9
作者：
通讯作者：

Busting the Myth of "Static vs Cidal": A Systemic Literature Review.

打破“静态与西达尔”的神话：系统文献综述。

DOI：
10.1093/cid/cix1127
发表时间：
2018
期刊：
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
影响因子：
0
作者：
Wald-Dickler,Noah;Holtom,Paul;Spellberg,Brad
通讯作者：
Spellberg,Brad

Defining the minimum inhibitory concentration of 22 rifamycins in iron limited, physiologic medium against Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae clinical isolates.